Role of Microglia in Cocaine Actions

小胶质细胞在可卡因作用中的作用

基本信息

批准号：
10062507
负责人：
Anne Schaefer
金额：
$ 24.09万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062507
关键词：
Ablation Acute Address Adult Agonist Apoptotic Behavior Behavioral Brain Brain region Cells Chronic Cocaine Corpus striatum structure Data Dendritic Spines Development Disease Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine Receptor Dorsal Drug Addiction Exhibits Feedback Follow-Up Studies Functional disorder Future Gene Expression Genes Genetic Genetic Transcription Human Investigation Knock-out Lead Mediating Mediator of activation protein Microglia Modeling Molecular Monitor Morphology Motor Activity Mus Mutant Strains Mice Neurobiology Neurons Nucleus Accumbens Opioid Pathogenesis Pathway interactions Pattern Pharmacologic Substance Phenotype Play Production Program Research Project Grants Public Health Receptor Signaling Regulation Relapse Role Scheme Self Administration Substance Use Disorder Synapses Testing Therapeutic Intervention addiction base behavioral response cell type cocaine exposure cocaine self-administration conditioned place preference density drug of abuse experimental study innovation neuronal survival novel receptor expression response single cell analysis transcriptome sequencing transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT– PROJECT 3 Project 3's objective is to address the role of microglia in modulating transcriptional adaptations in striatal medium spiny neurons (MSNs) triggered by cocaine self-administration. Microglia contribute to normal brain development and function by supporting neuronal survival and removing non-functional neurons and synapses. We have found that ablation of microglia causes a robust increase in behavioral responses to cocaine or to a D1 dopamine receptor agonist as well as an increase in dendritic spine density on MSNs. These findings suggest the hypothesis that microglia may function homeostatically to oppose conditions of excessive dopaminergic transmission, such as seen with cocaine exposure. We also have found that 10-15% of microglia in striatum, but not other brain regions, express the D1 receptor, raising the novel possibility of direct effects of cocaine (via increased dopaminergic transmission) on microglia. We now propose to fully characterize the influence of microglia in controlling behavioral responses to cocaine in self-administration models. This will include delineating a role for all microglia in striatum as well as a possible selective role played by D1+ microglia and by D1 receptor signaling within those microglia. We will next characterize the influence of microglia—again D1+ and D1- subpopulations—on the ability of cocaine self-administration to influence gene expression profiles in the D1-type and D2-type MSNs of striatum, separately examining nucleus accumbens and dorsal striatum. We will also characterize the changes in gene expression induced by cocaine self- administration in D1+ and D1- subpopulations of microglia themselves within striatum. These experiments are made possible by several novel lines of genetic mutant mice that enable the selective manipulation of microglial subpopulations within striatum combined with RNA-seq of isolated neuronal and microglia cell types—and even at the single cell level. These investigations of cocaine set the stage for follow up studies of microglia in opiate action as well as in humans with substance use disorders. Overall, the proposal has the potential to provide paradigm-shifting information about the role of microglia in the pathophysiology of drug addiction.

项目摘要/摘要 - 项目 3 项目 3 的目标是解决小胶质细胞在调节纹状体转录适应中的作用由可卡因自我给药触发的中型多棘神经元（MSN）有助于正常大脑。通过支持神经元存活并去除无功能的神经元和突触来促进发育和功能。我们发现，小胶质细胞的消融会导致对可卡因或某种物质的行为反应急剧增加。 D1 多巴胺受体激动剂以及 MSN 上树突棘密度的增加。提出这样的假设：小胶质细胞可能具有稳态功能，以对抗过度的条件多巴胺能传播，如接触可卡因时所见，我们还发现 10-15% 的小胶质细胞存在这种情况。在纹状体中表达 D1 受体，但在其他大脑区域中不表达，这提出了直接影响的新可能性可卡因（通过增加多巴胺能传递）对小胶质细胞的影响我们现在建议全面表征。小胶质细胞在控制自我给药模型中对可卡因的行为反应的影响。包括描绘纹状体中所有小胶质细胞的作用以及 D1+ 可能发挥的选择性作用接下来我们将描述小胶质细胞和这些小胶质细胞内 D1 受体信号传导的影响。小胶质细胞（同样是 D1+ 和 D1- 亚群）对可卡因自我施用影响基因的能力纹状体 D1 型和 D2 型 MSN 中的表达谱，分别检查伏隔核我们还将描述可卡因自身诱导的基因表达变化。这些实验是在纹状体内的小胶质细胞本身的 D1+ 和 D1- 亚群中进行给药。几个新的基因突变小鼠品系使之成为可能，这些小鼠能够选择性地操纵纹状体内的小胶质细胞亚群与分离神经元和小胶质细胞的 RNA-seq 相结合这些对可卡因的研究为后续研究奠定了基础。总体而言，该提案具有阿片类药物作用以及患有药物滥用障碍的人类的作用。有潜力提供关于小胶质细胞在药物病理生理学中的作用的范式转变信息瘾。